New achievement of the interdisciplinary work

Scientists from IBioBA and CIBION identified metabolic mechanisms that increase the malignancy of the kidney cancer cells. The article was published in the Journal of Proteome Research.

These findings could open up new therapeutic target options in the future.

Since several years the IBioBA performs studies together with the Center for Research in Bionanosciences (CIBION), in which the interdiscipline is of great value, complementing the knowledge of its scientists and taking advantage of the technological knowledge of both research centers to be able to address novel aspects of the topics they study. This time it is about the work between the group Neuro-endocrine tumors: cellular and molecular mechanisms led by Dr. Eduardo Arzt, also director of IBioBA, and the group of Bioanalytical Mass Spectrometry headed by Dr. María Eugenia Monge in CIBION.

Clear cell kidney cancer is a common subtype that takes its name because cells accumulate lipids in droplet form. The cells are characterized because as they become malignant, they acquire  changes in their metabolism such as oxidative stress or the deposition of lipids. In previous laboratory and clinical studies, the IBioBA group discovered that in patients with mutations in the VHL gene, which predisposes to the development of renal carcinoma, a protein called RSUME had pro-tumoral effects, triggering the formation of blood vessels and, consequently, increasing their aggressiveness.

However, this data was not enough to describe what happens to these cells when they increase their malignancy. They have a powerful capacity for metabolic adaptation that allows them to seek alternative energy routes to develop or resist therapies. Based on this premise, the teams set out to detect which other mechanisms were altered due to the increase in RSUME that stimulated cancer progression.

The approach was to design a metabolite analysis method at CIBION using an undirected metabolomics approach, using the ultra-high-performance liquid chromatography technique coupled to high-resolution mass spectrometry in combination with statistical analysis models, which allowed to differentiate cells with different amounts of RSUME in samples collected at IBioBA.

Metabolic pathways

Cancer cells grow very fast so that the available oxygen is not enough for them to grow, therefore, they compensate for this shortage with biochemical reactions that allow them to produce energy outside the mitochondria (main place of energy production) such as aerobic glycolysis. This alteration of its normal functioning produces responses that increase its malignant factors and RSUME is associated with this result.

From the study carried out by both research groups, two metabolic pathways were identified that were influenced by the presence of RSUME. On the one hand, the antioxidant defense produced by the glutathione molecule, which is increased in cells with a lower presence of RSUME. This causes them to become more sensitive to treatment with glutathione inhibitors and, thus, RSUME could function as a predictive marker for the success of therapies with these inhibitors.

The other metabolic pathway is the synthesis of fatty acids whose enzymes are increased in cells with more RSUME, but also presents other alterations in the use of nutrients in the cell.

Both situations are an indicator towards malignancy in this type of cancer, therefore cells with more RSUME, as is the case in many patients, present differences in important metabolic pathways that, after future studies, could be the target of therapies or possible predictive marker of therapies in clear cell renal cancer.

Teamwork

In 2017, the IBioBA began collecting samples of modified kidney cancer cell lines with and without RSUME. The collection of the samples was carefully planned with the CIBION team who then analyzed them until mid-2019. During this process, there was evidence of metabolic changes associated with the progression of kidney cancer. Once the CIBION team validated the chemical identities of the metabolites associated with changes in RSUME levels through mass spectrometry experiments, the biological validation tests were carried out at the IBioBA.

The value of scientific collaborations

Regarding interdisciplinary work, Dr. María Eugenia Monge, who leads the CIBION Bioanalytical Mass Spectrometry Group, comments that “this type of collaboration between researchers with different training and expertise enriches both CIBION and IBioBA.” And she adds: “We hope that these encouraging results will allow us to carry out new projects together.”

For his part, Eduardo Arzt, goes along the same lines and adds: “The work with Maria Eugenia Monge’s team from the CIBION was very enriching and stimulating for us, we learned a lot about the techniques and forms of analysis that they use, that we they provide a powerful new tool to answer our questions“. The Director of IBioBA adds that “it strengthens the capacities of IBIoBA, demonstrating in practice the advantages of interdisciplinary work, an increasing value today in research center designs”.

You can find this story published in Spanish in the website of the National Scientific and Tecnical Research Council (CONICET).